Inhibitory killer cell immunoglobulin-like receptors strengthen CD8+ T cell–mediated control of HIV-1, HCV, and HTLV-1

This article discusses how through experimentation it was determined that inhibitory killer cell immunoglobulin-like receptors (iKIRs) enhance CD8+ T-cell mediated control of human immunodeficiency virus type 1(HIV-1), hepatitis C virus (HCV), and Human T-cell leukemia virus type 1 (HTLV-1). Killer cell immunoglobulin-like receptors (KIRs) are transmembrane glycoproteins that can be activating or inhibitory. They bind to human-leukocyte antigen class 1 molecules (HLA-1)^1,2. Human-leukocyte antigen class 1 molecules are present on the surface of most cells in the body and present proteins from inside of the cell on the cells surface. During times of infection pathogen peptides rather than normal host cell peptides can be presented on the HLA-1 molecules on the cell surface so that certain leukocytes (immune cells) can bind to them. This binding then triggers signals that can activate an immune response. This study examines the effect of the presence of iKIRs of CD8+ T-cells and their interactions with these HLA-1 on the CD8+ T-cell mediated response to HIV-1, HCV, and HTLV-1. CD8+ T-cells are also known as cytotoxic T-cells. They target infected, unhealthy, or no longer needed cells and kill them. This is important during viral infections since viruses reside inside of host cells so the body’s way to eliminate a viral infection is to kill the infected cells. HIV-1 is a virus that is transmitted via bodily fluids that targets CD4+ T-cells. If HIV-1 is untreated it reduces the number of CD4+ T-cells in the body which reduces the body’s ability to fight off infection³. CD4+ T-cells are responsible for regulating the body’s immune response. HCV is a virus that causes infection and inflammation of the liver. Inflammation of the liver can impair its function. HCV can last a few weeks or can become a chronic, lifelong illness⁴. HTLV-1 is a virus that is generally asymptomatic until later in life when it can lead to diseases such as adult T-cell leukemia/lymphoma (ATL) and an incapacitating neurological disease (HTLV-associated myelopathy/tropical spastic paraparesis [HAM/TSP]), among other afflictions⁵. It has been shown that iKIR expression on CD8+ T-cells directly effects the cells longevity and function^6,7,8,9,10. In humans T-cells iKIR expression is associated with increased Bcl-2 levels which is a pro-survival molecule for T-cells^11,12,13. The goal of this study was to determine if iKIRs impact the CD8+ T-cell response in a clinically significant way.

The experiment operated on the fact that there is a well-documented associated between HLA-1 alleles and disease outcomes. So, if KIRs affect CD8+ T-cells they will affect HLA-1 disease associations. There are different alleles of the HLA-1 molecule that code for various types of HLA-1 molecules. Certain HLA-1 molecules that are a result of certain alleles interact with certain KIRs which results in different effects on the immune response and outcomes of the disease. Some alleles of the HLA-1 gene are protective and others are detrimental regarding the viral infections studied as shown in table 1.

These HLA-1 disease associations were studied to see how iKIRs affect them. The researchers showed that the HLA-B*57 allele’s protective effect in respect to HIV-1 was enhanced when there were more iKIRs and when the KIRs could bind better, which correlates to stronger signaling. This shows that a strong inhibitory signal that the protective function of HLA-B*57 was sustained which they determined by determining the viral load (amount of virus) in the sample after a certain amount of time. The sample with a strong inhibitory signal showed a low viral load and thus showed that the protective effect of HLA-B*57 was increased by the presence of iKIRs. The sample without a strong inhibitory signal from iKIRs did not show this low viral load and thus showed that the protective effects of HLA-B*57 were not enhanced in the absence of iKIRs. It was also shown that iKIRs enhance the protective effects of HLA-B*57 in HCV as well. The researchers also studied how iKIR signaling effected the detrimental association of the HLA-B*35Px allele in respect to HIV-1. They showed that in individuals that exhibited weak inhibitory signaling from iKIRs the viral load was eroded over time, showing a decreasing in infection. Whereas in individuals that had a strong inhibitory signal from iKIRs the viral load was maintained overtime, showing no decrease in infection. This shows that iKIRs enhance the detrimental effects of HLA-B*35Px since in individuals who have strong signaling from iKIRs binding to this molecule there is a maintained viral load and thus maintained infection.

The experiments performed in this study show that iKIR signaling enhances the effects of HLA-1 molecules regardless of if they are protective or detrimental. CD8+ T-cells are responsible for killing cells, in times of infection they kill infected cells and thus fight off infection and reduce viral load. iKIRs are present on CD8+ T-cells and bind to HLA-1 molecules to send signals to the CD8+ T-cells that alter its function and the immune response mounted by these cells. So, this research shows that the interactions between the iKIRs and the HLA-1 alleles influence the immune response via these CD8+ T-cells. The protective effects of some alleles are produced in some cases via the mechanism of increasing the longevity of these T-cells discussed in the beginning of this post. This would result in a stronger immune response and thus a decrease in infection and viral load as shown when iKIRs enhanced the protective effects of certain HLA-1 alleles. The detrimental effects of some on the HLA-1 alleles could the result of the iKIR signaling that occurs when the HLA-1 molecule is bound being inhibitory to the CD8+ T-cell and thus preventing a full immune response from being mounted towards the virus. This could explain the results of in samples with low inhibitory signaling in respect to the detrimental HLA-B*35Px allele there was a lower viral load and thus less infection. The viruses discussed in this study, HIV-1, HCV, and HTLV-1 are all characterized by chronic immune activation which has been associated with CD8+ T cell exhaustion^14,15,16,17. CD8+ T-cell exhaustion occurs when the cells get large amount of activating signals and proliferate relentlessly to where the progeny are no longer functional, and no memory cells are produced. Chronic activation is associated with increased KIR expression in T-cells^6-10,18,19. The research in this study as well as the material provided from previous studies show that iKIR-HLA-1 interactions are clinically significant. This means that these interactions could be the targets of new treatments and therapies for the viral infections discussed here as well as others. For example, work could be done to explore the possibility of blocking the interaction between iKIRs and the detrimental HLA-1 alleles so that the iKIR signaling cannot enhance the alleles detrimental effects.

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